Novel compounds

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof:  
                 
 
wherein, R 1 , R 2 , P, p and n are as defined in the specification, a process for preparing such compounds, a pharmaceutical composition containing such compounds and the use of such compounds in medicine.

This invention relates to novel compounds, especially urea derivatives,having pharmacological activity, processes for their preparation, tocompositions containing them and to their use in the treatment ofvarious disorders.

Vanilloids are a class of natural and synthetic compounds which arecharacterised by the presence of a vanillyl (3-hydroxy 4-methoxyphenyl)group or a functionally equivalent group. Vanilloid Receptor (VR1),whose function is modulated by such compounds, has been widely studiedand is extensively reviewed by Szallasi and Blumberg (The AmericanSociety for Pharmacology and Experimental Therapeutics, 1999, Vol. 51,No. 2.).

A wide variety of Vanilloid compounds of different structures are knownin the art, for example those disclosed in European Patent ApplicationNumbers EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB2226313 and International Patent Application, Publication Number WO92/09285. Particularly notable examples of vanilloid compounds orvanilloid receptor modulators are capsaicin, namely trans8-methyl-N-vanillyl-6-nonenamide, isolated from the pepper plant,capsazepine (Tetrahedron, Vol. 53, No. 13, pp. 4791- 4814, 1997) andolvanil-N-(3-methoxy-4-hydroxy-benzyl)oleamide (J. Med. Chem. 1993, 36,2595-2604).

U.S. Pat. No. 3,424,760 and U.S. Pat. No. 3,424,761 both describe aseries of 3-Ureidopyrrolidines that are said to exhibit analgesic,central nervous system, and pyschopharmacologic activities. Thesepatents specifically disclose the compounds1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl)urea respectively.

International Patent Applications, Publication Numbers WO 02/08221, WO02/16317, WO 02/16318 and WO 02/16319 each disclose certain vanilloidreceptor antagonists and their use in the treatment of diseasesassociated with the activity of the vanilloid receptor.

Co-pending International Patent Application Number PCT/EP02/04802discloses a series of urea derivatives and their use in the treatment ofdiseases associated with the activity of the vanilloid receptor.

A structurally novel class of compounds has now been found which alsopossess Vanilloid receptor (VR1) antagonist activity. The presentinvention therefore provides, in a first aspect, a compound of formula(I) or a pharmaceutically acceptable salt or solvate thereof:

wherein,

-   P is phenyl, naphthyl or heterocyclyl;-   R¹ is selected from —H, halo, alkyl, alkoxy, cycloalkyl, aralkyl,    aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN, —NO₂, —OH, —OCF₃,    —CF₃, —NR⁵R⁶, —S(O)_(m)R⁷, —S(O)₂NR⁵R⁶, —OS(O)₂R⁷, —OS(O)₂CF₃,    —O(CH₂)_(x)NR⁵R⁶, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl,    —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(x)OR⁷, —C(O)(CH₂)_(x)NR⁵R⁶,    —C(O)alkoxy, —C(O)NR⁵R⁶, —(CH₂)_(x)C(O)alkoxy, —(CH₂)_(x)OC(O)R⁷,    —(CH₂)_(x)OR⁷, —(CH₂)_(x)R⁵R⁶, —(CH₂)_(x)C(O)NR⁵R⁶,    —(CH₂)_(x)N(R⁵)C(O)R⁷, —(CH₂)_(x)S(O)₂NR⁵R⁶, —(CH₂)_(x)N(R⁵)S(O)₂R⁷,    -ZAr, —(CH₂)_(x)S(O)₂R⁷, —(OCH₂)_(x)S(O)₂R⁷, —N(R⁵)S(O)₂R⁷,    —N(R⁵)C(O)R⁷, —(CH₂)_(x)N(R⁵)S(O)₂R⁷, —(CH₂)_(x)N(R⁵)C(O)R⁷ or    —(CH₂)_(x)C(O)alkyl;-   R² is the group:-   X is a bond, C, O or NR⁸;-   R³ is selected from —H, halo, alkyl, alkoxy, cycloalkyl, aryl,    aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, —CN, —NO₂,    —OH, —OCF₃, —CF₃, —NR⁵R⁶, —S(O)_(m)R⁷, —S(O)₂NR⁵R⁶, —OS(O)₂R⁷,    —OS(O)₂CF₃, —O(CH₂)_(x)NR⁵R⁶, —C(O)CF₃, —C(O)alkyl, —C(O)cycloalkyl,    —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(x)OR⁷, —C(O)(CH₂)_(x)NR⁵R⁶,    —C(O)alkoxy, —C(O)NR⁵R⁶, —(CH₂)_(x)C(O)alkoxy, —(CH₂)_(x)OC(O)R⁷,    —(CH₂)_(x)OR⁷, —(CH₂)_(x)R⁵R⁶, —(CH₂)_(x)C(O)NR⁵R⁶,    —(CH₂)_(x)N(R⁵)C(O)R⁷, —(CH₂)_(x)S(O)₂NR⁵R⁶, —(CH₂)_(x)N(R⁵)S(O)₂R⁷,    -ZAr, —(CH₂)_(x)S(O)₂R⁷, —(OCH₂)_(x)S(O)₂R⁷, —N(R⁵)S(O)₂R⁷,    —N(R⁵)C(O)R⁷, —(CH₂)_(x)N(R⁵)S(O)₂R⁷, —(CH₂)_(x)N(R⁵)C(O)R⁷ or    —(CH₂)_(x)C(O)alkyl;-   R⁴ is hydrogen or alkyl;-   R⁵ and R⁶ may be the same or different and represent H or alkyl or    R⁵ and R⁶ together with the atoms to which they are attached form a    C₃₋₆azacycloalkane, C₃₋₆(2-oxo)azacycloalkane ring or C₅₋₈    polymethylene chain optionally interrupted by heteroatoms such as O    or —NR⁸;-   Z is O, S or NR⁸;-   R⁷ is alkyl or aryl;-   R⁸ is hydrogen, alkyl or aryl;-   n is 2, 3, 4, 5 or 6;-   p is 0, 1, 2, 3 or 4;-   q is 0, 1, 2 or 3;-   r is 0, 1 or 2; and-   x is 0, 1, 2, 3, 4, 5 or 6.

Suitably, P is phenyl, naphthyl, cinnolinyl or isoquinolinyl. When P isnaphthyl, a preferred group is naphth-1-yl. Preferably, P is phenyl.

Suitably, R¹ is halo, alkyl, alkoxy, —C(O)alkyl, —NO₂, —CF₃, —CN or—OCF₃. More suitably, R¹ is halo, alkyl, —C(O)alkyl or —OCF₃.Preferably, R¹ is halo, —C(O)Me or —OCF₃.

Suitably, R² is

-   Preferably, R² is dihydroindolyl, tetrahydroydroquinolinyl or    dihydrobenzo[1,4]oxazinyl. Most preferably, R² is    2,3-dihydroindol-1-yl, 3,4-dihydro-2H-quinolin-1-yl or    2,3-dihydrobenzo[1,4]oxazin-4-yl.

Suitably, R³ is halo, alkyl, alkoxy, —CF₃, —CN or aryl. More suitably,R³ is halo or alkyl. Preferably, R³ is fluoro or methyl. Mostpreferably, R³ is a methyl or fluoro substituted at either the 4- or5-position on the dihydroindole ring, a methyl group substituted on the6-position of the dihydroquinolinyl ring or a methyl group substitutedon the 7-position of the dihydrobenzo[1,4]oxazinyl ring.

Suitably, R⁴ is alkyl. Preferably, R⁴ is methyl.

Suitably, R⁵ is alkyl. Preferably, R⁵ is methyl.

When p is 2 or 3 the groups R¹ may be the same or different. Preferably,p is 1 or 2.

When r is 2 the groups R⁴ may be the same or different. Preferably, r is0 or 1.

Preferably, n is 2 or 3. Most preferably, n is 2.

Preferably, q is 1 or 2. Most preferably, q is 1.

Preferably, x is O.

Particularly preferred compounds according to the invention includeexamples E1 to E58 or a pharmaceutically acceptable salt or solvatethereof.

The compounds of the formula (I) can form acid addition salts withacids, such as conventional pharmaceutically acceptable acids, forexample maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

Compounds of formula (I) may also form solvates such as hydrates, andthe invention also extends to these forms. When referred to herein, itis understood that the term ‘compound of formula (I)’ also includesthese forms.

Certain compounds of formula (I) are capable of existing instereoisomeric forms including diastereomers and enantiomers and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated one from the other by the usual methods, or any given isomermay be obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof.

As indicated above, the compounds of formula (I) can form salts,especially pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts are those use conventionally in the art and includethose described in J. Pharm. Sci., 1977, 66, 1-19, such as acid additionsalts.

Suitable pharmaceutically acceptable salts include acid addition salts.

Suitable pharmaceutically acceptable acid addition salts include saltswith inorganic acids such, for example, as hydrochloric acid,hydrobromic acid, orthophosphoric acid or sulphuric acid, or withorganic acids such, for example as methanesulphonic acid,toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citricacid, fumaric acid, malic acid, succinic acid, salicylic acid, maleicacid, glycerophosphoric acid or acetylsalicylic acid.

The salts and/or solvates of the compounds of the formula (I) which arenot pharmaceutically acceptable may be useful as intermediates in thepreparation of pharmaceutically acceptable salts and/or solvates ofcompounds of formula (I) or the compounds of the formula (I) themselves,and as such form another aspect of the present invention.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and if crystalline, may be optionally hydrated orsolvated. This invention includes in its scope stoichiometric hydratesas well as compounds containing variable amounts of water.

Suitable solvates include pharmaceutically acceptable solvates, such ashydrates.

Solvates include stoichiometric solvates and non-stoichiometricsolvates.

As used herein the term “alkyl” as a group or part of a group refers toa straight or branched chain saturated aliphatic hydrocarbon radicalcontaining 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms. Suchalkyl groups in particular include methyl (“Me”), ethyl (“Et”), n-propyl(“Pr^(n)”), iso-propyl (“Pr^(i)”), n-butyl (“Bu^(n)”), sec-butyl(“Bu^(s)”), tert-butyl (“Bu^(t)”), pentyl and hexyl. Where appropriate,such alkyl groups may be substituted by one or more groups selected fromhalo (such as fluoro, chloro, bromo), —CN, —CF₃, —OH, —OCF₃, C₂₋₆alkenyl, C₃₋₆ alkynyl, C₁₋₆ alkoxy, aryl and di-C₁₋₆ alkylamino.

As used herein, the term “alkoxy” as a group or part of a group refersto an alkyl ether radical, wherein the term “alkyl” is defined above.Such alkoxy groups in particular include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Whereappropriate, such alkoxy groups may be substituted by one or more groupsselected from halo (such as fluoro, chloro, bromo), —CN, —CF₃, —OH,—OCF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ alkynyl, aryl and di-C₁₋₆alkylamino.

As used herein, the term “aryl” as a group or part of a group refers toa carbocyclic aromatic radical (“Ar”). Suitably such aryl groups are 5-6membered monocyclic groups or 8-10 membered fused bicyclic groups,especially phenyl (“Ph”), biphenyl and naphthyl, particularly phenyl.

The term “halo” is used herein to describe, unless otherwise stated, agroup selected from fluorine (“fluoro”), chlorine (“chloro”), bromine(“bromo”) or iodine (“iodo”).

The term “naphthyl” is used herein to denote, unless otherwise stated,both naphth-1-yl and naphth-2-yl groups.

The term ‘heterocyclyl’ is used herein to describe, unless otherwisestated, groups comprising one or more rings which may be saturated,unsaturated or aromatic and which may independently contain one or moreheteratoms in each ring. Examples of suitable heterocyclyl groupsinclude, but are not limited to, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl,dihydrobenzofuranyl, furanyl, furazanyl, imidazolyl, 1H-indazolyl,indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, phthalazinyl, pteridinyl,purinyl, pyrazinyl, pyrazolyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl andxanthenyl.

The present invention also provides, in a further aspect, a process forthe preparation of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof, which process comprises coupling acompound of formula (II):

in which R¹, P and p are as defined in formula (I), with a compound offormula (III):B—(CH₂)_(n)—R²   (III)in which R² and n are as defined in formula (I) and A and B contain theappropriate functional groups which are capable of reacting together toform the urea moiety;and optionally thereafter if appropriate:

-   (i) removing any protecting groups;-   (ii) forming a pharmaceutically acceptable salt or solvate of the    compound so formed.

Suitable examples of appropriate A and B groups include:

-   (a) A is —N═C═O and B is NH₂; or-   (b) A is NH₂ and B is —N═C═O; or-   (c) A is NH₂ and B is NH₂ together with an appropriate urea forming    agent.

In process (a) or (b) the reaction is carried out in an inert solventsuch as dichloromethane or acetonitrile.

In process (c) the urea forming agent can be carbonyl diimidazole orphosgene. The reaction may be performed in an inert organic solvent suchas dimethylformamide, tetrahydrofuran or dichloromethane at ambient orelevated temperature. The reaction is typically performed in thepresence of a base such as triethylamine or pyridine.

An alternative method of synthesis of the unsymmetrical urea compoundsof formula (I) is from a diaryl carbonate, via the correspondingcarbamate. Such a methodology is described by Freer et al. (SyntheticCommunications, 26(2), 331 - 349, 1996). It will be appreciated thatsuch a methodology could readily be adapted for the preparation ofcompounds of formula (I).

Those skilled in the art will appreciate that it may be necessary toprotect certain groups in the synthesis of compounds of formula (I).Suitable protecting groups and methods for their attachment and removalare conventional in the art of organic chemistry, such as thosedescribed in Greene T. W. ‘Protective groups in organic synthesis’ NewYork, Wiley (1981).

Compounds of formulae (II) and (III) are commercially available or maybe prepared according to known methods or analogous to known methods.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

Compounds of formula (I) and their pharmaceutically acceptable salts orsolavtes thereof have Vanilloid receptor antagonist (VR1) activity andare believed to be of potential use for the treatment or prophylaxis ofcertain disorders, or treatment of the pain associated with them, suchas: pain, chronic pain, neuropathic pain, postoperative pain,postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceralpain, cancer pain, algesia, neuralgia, dental pain, headache, migraine,neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-relatedneuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica,nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain,multiple sclerosis, respiratory diseases, asthma, cough, COPD, bronchoconstriction, inflammatory disorders, oesophagitis, heart burn,Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder(GERD), stomach and duodenal ulcers, functional dyspepsia, irritablebowel syndrome, inflammatory bowel disease, colitis, Crohn's disease,pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic,urinary incontinence, cystitis, burns, itch, psoriasis, pruritis, emesis(hereinafter referred to as the “Disorders of the Invention”).

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, for use as atherapeutic substance, in particular in the treatment or prophylaxis ofthe Disorders of the Invention.

In particular, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof or a solvate thereof for use inthe treatment or prophylaxis of pain and urinary incontinence.

The invention further provides a method of treatment or prophylaxis ofthe Disorders of the Invention, in mammals including humans, whichcomprises administering to the sufferer a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral, rectal administration orintravesical adminstration to the bladder and, as such, may be in theform of tablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable or infusable solutions,suspensions or suppositories. Orally administrable compositions aregenerally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt or solvate thereof and a sterile vehicle. The compound, dependingon the vehicle and concentration used, can be either suspended ordissolved in the vehicle. In preparing solutions, the compound can bedissolved for injection and filter sterilised before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are dissolved inthe vehicle. To enhance the stability, the composition can be frozenafter filling into the vial and the water removed under vacuum.Parenteral suspensions are prepared in substantially the same manner,except that the compound is suspended in the vehicle instead of beingdissolved, and sterilization cannot be accomplished by filtration. Thecompound can be sterilised by exposure to ethylene oxide beforesuspension in a sterile vehicle. Advantageously, a surfactant or wettingagent is included in the composition to facilitate uniform distributionof the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors. Forsystemic administration, dosage levels from 0.01 mg to 100 mg perkilogramme of body weight are useful in the treatment of pain. However,as a general guide suitable unit doses may be 0.05 to 1000 mg, moresuitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5and 0.1 to 250 mg; and such unit doses may be administered more thanonce a day, for example two or three a day, so that the total dailydosage is in the range of about 0.5 to 1000 mg; and such therapy mayextend for a number of weeks or months.

When administered in accordance with the invention, no unacceptabletoxicological effects are expected with the compounds of the invention.

The following Examples illustrate the preparation of the compounds ofthe invention and are not intended to be limiting in any way.

Abbreviations:

-   AIBN—azoisobutyronitrile-   DMF—dimethylformamide-   MgSO₄—magnesium sulfate-   THF—tetrahydrofuran

Description 1 1-(2-Aminoethyl)indoline (D1)

A mixture of indoline (15 g, 0.126 mol) and 2-bromoethylaminehydrobromide (12.9 g, 0.063 mol) in toluene was heated at reflux for 18h. After cooling solvent was removed under reduced pressure and theresidue dissolved in water. Basification using aqueous potassiumcarbonate was followed by solvent extraction using dichloromethane.Organic phase was separated, dried over MgSO₄, filtered and concentratedunder reduced pressure to leave an oil. Chromatography on silica geleluting with dichloromethane and methanol (gradient elution, maximum20%) afforded the title compound as yellow oil (5.45 g, 27%).

Description 2 4-Methylindoline (D2)

To a solution of 4-methylindole (1 g, 7.6 mmol) in glacial acetic acid(10 ml) was added portionwise sodium cyanoborohyride (1.44 g, 0.023 mol)over 15 mins under an argon atmosphere. Stirring was continued for 18 hand water (100 ml) added. Basification using aqueous sodium hydroxidewas followed by solvent extraction using dichloromethane. Organic phasewas separated, dried (MgSO₄), filtered and concentrated under reducedpressure to leave an oil (0.98 g, 97%).

Description 3 1-(2-Aminoethyl)-4-methylindoline (D3)

-   The title compound was prepared from 4-methylindoline (D2) using the    procedure outlined for Description 1 (0.63 g, 96%).

Description 4 5-Fluoroindoline (D4)

The title compound was prepared from 5-fluoroindole using the procedureoutlined for Description 2 (4.1 g, 82%).

Description 5 1-(2-Aminoethyl)-5-fluoroindoline (D5)

The title compound was prepared from 5-fluoroindoline (D4) using theprocedure outlined for Description 1 (2.5 g, 92%).

Description 6 5-Methylindoline (D6)

The title compound was prepared from 5-methylindole using the procedureoutlined for Description 2 (2.5 g, 50%).

Description 7 1-(2-Aminoethyl)-5-methylindoline (D7)

The title compound was prepared from 5-methylindoline (D6) using theprocedure outlined for Description 1 (1.35 g, 82%).

Description 8 4-Fluoroindoline (D8)

The title compound was prepared from 4-fluoroindole using the procedureoutlined for Description 2 (1.24 g, 61%).

Description 9 1-(2-Aminoethyl)-4-fluoroindoline (D9)

The title compound was prepared from 4-fluoroindoline (D8) using theprocedure outlined for Description 1 (0.7 g, 97%).

Description 10 N-(2-Bromo-4-fluorophenyl)acetamide (D10)

To a solution of 2-bromo-4-fluoroaniline (7.35 g, 0.039 mol) andtriethylamine (11 ml) in dichloromethane (30 ml) was added a solution ofacetyl chloride (2.8 ml) in dichloromethane (20 ml) whilst cooling (icebath) over a period 20 min. Stirring was continued for 6 h and thendichloromethane partitioned with water. The dichloromethane layer wasseparated, dried (MgSO₄), filtered and concentrated under reducedpressure to afford the product as a white solid (4.61 g, 49%).

Description 11 N-(2-Bromo-4-fluorophenyl)-N-(2-methylallyl)acetamide(D11)

To a cooled solution (ice bath) of (D10) (4.6 g, 0.021 mol) in dry DMF(30 ml) was added sodium hydride (60% dispersion in oil, 0.89 g, 0.022mol) under an argon atmosphere. After stirring for 10 min3-bromo-2-methylpropene was added and the reaction stirred at ambienttemperature for 18 h. DMF was removed under reduced pressure and theresidue partitioned between diethyl ether and water. The organic layerwas separated, dried (MgSO₄), filtered and concentrated under reducedpressure to afford an oil. Chromatography on silica gel eluting withdiethyl ether afforded the product as a clear oil (5.5 g, 91%).

Description 12 1-(5-Fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone(D12)

A solution of (D11) (2.2 g, 8 mmol) in toluene (30 ml) was treated withAIBN (catalytic amount, 30 mg) followed by tributyltin hydride (2.6 ml,0.01 mol) in toluene (10 ml). Reaction was stirred for 20 min at ambienttemperature and then warmed to 50° C. for 90 min. After cooling, thereaction mixture was partitioned with water. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated under reducedpressure to afford an oil. Chromatography on silica gel eluting withdiethyl ether and hexane (gradient elution, maximum 50%), afforded theproduct as a white solid (0.56 g, 35%).

Description 13 5-Fluoro-3,3-dimethylindoline (D13)

A solution of (D12) (0.78 g, 3.8 mmol) in ethanol (10 ml) and 2M HCl (25ml) was heated at 85° C. for 2 h and cooled. Basification using sodiumhydrogen carbonate was followed by solvent extraction usingdichloromethane. Organic phase was separated, dried (MgSO₄), filteredand concentrated under reduced pressure to leave an oil (0.55 g, 87%).

Description 14 2-(5-Fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)ethylamine(D14)

The title compound was prepared from (D13) using the procedure outlinedfor Description 1 (0.14 g, 43%).

Description 15 2-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)ethylamine

The title compound was prepared from6-methyl-1,2,3,4-tetrahydroquinoline using the procedure outlined forDescription 1 (5.85 g, 44%).

Description 16 (5-Methyl-2-nitrophenoxy)-acetic acid, ethyl ester (D16)

A solution of 5-methyl-2-nitrophenol (10 g, 0.065 mol) and ethylbromoacetate (7.25 ml) in acetone (200 ml) containing powdered potassiumcarbonate (9.91 g) was refluxed for 18 h and cooled. The solid wasfiltered off and the filtrate concentrated under reduced pressure toafford the product as a light yellow solid (15.22 g, 98%).

Description 17 7-Methyl4H-benzo[1,4]oxazin-3-one (D17)

A solution of (D16) (15.2 g, 0.064 mol) in ethanol (80 ml) andcyclohexene (10 ml) containing 10% palladium on charcoal (0.5 g) washeated at reflux for 27 h and cooled. Catalyst was filtered off and thefiltrate concentrated under reduced pressure to afford the compound as awhite solid (6.25 g, 60%).

Description 18 7-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine (D18)

A suspension of (D17) (6.0 g, 0.037 mol) in dry THF (50 ml) was treatedwith borane. THF complex (2.5 eq., 100 ml). The resulting solution wasthen heated at reflux for 3 h, cooled, basified using aqueous potassiumcarbonate (10%, 150 ml) and extracted using dichloromethane. Organicphase was separated, dried (MgSO₄), filtered and concentrated underreduced pressure to leave an oil. Chromatography on silica gel elutingwith dichloromethane afforded the product as an oil (5.4 g, 98%).

Description 19 2-(7-Methyl-2,3-dihydrobenzo[1,4]oxazin4-yl)ethylamine(D19)

The title compound was prepared from7-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (D18) using the procedureoutlined for Description 1 (2.20 g, 64%).

Description 20 (5-Fluoro-2-nitrophenoxy)-acetic acid, ethyl ester (D20)

The title compound was prepared from 5-fluoro-2-nitrophenol using theprocedure outlined in Description 16 (15.17 g, 98%).

Description 21 7-Fluoro-4H-benzo[1,4]oxazin-3-one (D21)

The title compound was prepared from (D20) using the procedure outlinedfor Description 17 (8.15 g, 79%).

Description 22 7-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazine (D22)

The title compound was prepared from (D21) using the procedure outlinedfor Description 18 (7.15 g, 98%).

Description 23 2-(7-Fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)ethylamine(D23)

The title compound was prepared from (D22) using the procedure outlinedfor Description 19 (2.15 g, 56%).

EXAMPLE 1N-(2-Bromophenyl)-N′-[2-(7-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)ethyl]urea(E1)

To a solution of 2-(7-fluoro-2,3-dihdrobenzo[1,4]oxazin-4-yl)ethylamine(D23) (0.1 g, 0.5 mmol) in dichloromethane (3 ml) was added2-bromophenyl isocyanate (101 mg, 0.5 mmol) in dichloromethane (2 ml).Reaction was stirred for 18 h and the precipitated solid was filteredoff and dried to afford the title compound as a white solid (190 mg,96%).

¹H NMR (400 MHz, CDCl₃) δ7.96 (d, 1H), 7.51 d, 1H), 7.28 (m, 1H), 6.94(m, 1H), 6.67 (m, 2H), 6.54 (m, 2H), 4.98 (br, 1H), 4.21 (m, 2H), 3.50(m, 2H), 3.40 (m, 2H), 3.32 (m, 2H). MH⁺ 394, 396.

The following examples (Table 1) were prepared using a similar procedureto that outlined for E1 with the appropriate amine and isocyanate. TABLE1 Example MH⁺ N-(4-Fluorophenyl)-N′-[2-(2,3-dihydroindol-1- 300yl)ethyl]urea (E2) N-(3,4-Difluorophenyl)-N′-[2-(2,3-dihydroindol-1- 318yl)ethyl]urea (E3)N-(2-Methyl-3-chlorophenyl)-N′-[2-(2,3-dihydroindol-1- 330, 332yl)ethyl]urea (E4) N-(2,3-Dichlorophenyl)-N′-[2-(2,3-dihydroindol-1-314, 316 yl)ethyl]urea (E5) N-(2-Bromophenyl)-N′-[2-(2,3-dihydroindol-1-360, 362 yl)ethyl]urea (E6)N-(2-(Trifluoromethoxy)phenyl)-N′-[2-(2,3-dihydroindol-1- 366yl)ethyl]urea (E7) N-(2-Iodophenyl)-N′-[2-(2,3-dihydroindol-1- 408yl)ethyl]urea (E8) N-Phenyl-N′-[2-(4-methyl-2,3-dihydroindol-1- 296yl)ethyl]urea (E9)N-(4-Fluorophenyl)-N′-[2-(4-methyl-2,3-dihydroindol-1- 314 yl)ethyl]urea(E10) N-(2-Chlorophenyl)-N′-[2-(4-methyl-2,3-dihydroindol-1- 330, 332yl)ethyl]urea (E11)N-(3,4-Difluorophenyl)-N′-[2-(4-methyl-2,3-dihydroindol- 3321-yl)ethyl]urea (E12)N-(3-Acetylphenyl)-N′-[2-(4-methyl-2,3-dihydroindol-1- 338 yl)ethyl]urea(E13) N-(2-Methyl-3-chlorophenyl)-N′-[2-(4-methyl-2,3- 344, 346dihydroindol-1-yl)ethyl]urea (E14)N-(2,3-Dichlorophenyl)-N′-[2-(4-methyl-2,3-dihydroindol-1- 364, 366yl)ethyl]urea (E15)N-(2,5-Dichlorophenyl)-N′-[2-(4-methyl-2,3-dihydroindol-1- 364, 366yl)ethyl]urea (E16)N-(2-Bromophenyl)-N′-[2-(4-methyl-2,3-dihydroindol-1- 374, 376yl)ethyl]urea (E17) N-(2-(Trifluoromethoxy)phenyl)-N′-[2-(4-methyl-2,3-380 dihydroindol-1-yl)ethyl]urea (E18)N-(2-Iodophenyl)-N′-[2-(4-methyl-2,3-dihydroindol-1- 422 yl)ethyl]urea(E19) N-(2,5-Dichlorophenyl)-N′-[2-(5-methyl-2,3-dihydroindol-1- 364,366 yl)ethyl]urea (E20)N-(2-Bromophenyl)-N′-[2-(5-methyl-2,3-dihydroindol-1- 374, 376yl)ethyl]urea (E21)N-(4-Fluorophenyl)-N′-[2-(5-methyl-2,3-dihydroindol-1- 314 yl)ethyl]urea(E22) N-Phenyl-N′-[2-(4-fluoro-2,3-dihydroindol-1- 300 yl)ethyl]urea(E23) N-(4-Fluorophenyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 318yl)ethyl]urea (E24)N-(2-Chlorophenyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 334, 336yl)ethyl]urea (E25)N-(3,4-Difluorophenyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 336yl)ethyl]urea (E26)N-(3-Acetylphenyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 342 yl)ethyl]urea(E27) N-(2-Methyl-3-chlorophenyl)-N′-[2-(4-fluoro-2,3- 348, 350dihydroindol-1-yl)ethyl]urea (E28)N-(1-Naphthyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 350 yl)ethyl]urea(E29) N-(2,3-Dichlorophenyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 368,370 yl)ethyl]urea (E30)N-(2,5-Dichlorophenyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 368, 370yl)ethyl]urea (E31)N-(2-Bromophenyl)-N′-[2-(4-fluoro-2,3-dihydroindol-1- 378, 380yl)ethyl]urea (E32) N-(2-(Trifluoromethoxy)phenyl)-N′-[2-(4-fluoro-2,3-383 dihydroindol-1-yl)ethyl]urea (E33)N-Phenyl-N′-[2-(5-fluoro-2,3-dihydroindol-1- 300 yl)ethyl]urea (E34)N-(4-Fluorophenyl)-N′-[2-(5-fluoro-2,3-dihydroindol-1- 318 yl)ethyl]urea(E35) N-(2-Chlorophenyl)-N′-[2-(5-fluoro-2,3-dihydroindol-1- 334, 336yl)ethyl]urea (E36)N-(3,4-Difluorophenyl)-N′-[2-(5-fluoro-2,3-dihydroindol-1- 336yl)ethyl]urea (E37)N-(3-Acetylphenyl)-N′-[2-(5-fluoro-2,3-dihydroindol-1- 342 yl)ethyl]urea(E38) N-(2-Methyl-3-chlorophenyl)-N′-[2-(5-fluoro-2,3- 334, 336dihydroindol-1-yl)ethyl]urea (E39)N-(1-Naphthyl)-N′-[2-(5-fluoro-2,3-dihydroindol-1- 350 yl)ethyl]urea(E40) N-(2,5-Dichlorophenylphenyl)-N′-[2-(5-fluoro-2,3- 368, 370dihydroindol-1-yl)ethyl]urea (E41)N-(2-Bromophenyl)-N′-[2-(5-fluoro-2,3-dihydroindol-1- 378, 380yl)ethyl]urea (E42) N-(2-(Trifluoromethoxy)phenyl)-N′-[2-(5-fluoro-2,3-384 dihydroindol-1-yl)ethyl]urea (E43)N-(2-Iodophenyl)-N′-[2-(5-fluoro-2,3-dihydroindol-1- 426 yl)ethyl]urea(E44) N-(2-Bromophenyl)-N′-[2-(6-methyl-3,4-dihydro-2H-quinolin- 388,390 1-yl)ethyl]urea (E45)N-(4-Fluorophenyl)-N′-[2-(6-methyl-3,4-dihydro-2H-quinolin- 3291-yl)ethyl]urea (E46)N-(2-Methyl-3-chlorophenyl)-N′-[2-(6-methyl-3,4-dihydro- 358, 3602H-quinolin-1-yl)ethyl]urea (E47)N-(1-Naphthyl)-N′-[2-(6-methyl-3,4-dihydro-2H-quinolin-1- 360yl)ethyl]urea (E48)N-(2,3-Dichlorophenyl)-N′-[2-(6-methyl-3,4-dihydro-2H- 378, 380quinolin-1-yl)ethyl]urea (E49)N-(2,5-Dichlorophenyl)-N′-[2-(6-methyl-3,4-dihydro-2H- 378, 380quinolin-1-yl)ethyl]urea (E50) N-(4-Fluorophenyl)-N′-[2-(7-methyl-2,3-330 dihydrobenzo[1,4]oxazin-4-yl)ethyl]urea (E51)N-(2-Bromophenyl)-N′-[2-(7-methyl-2,3- 390, 392dihydrobenzo[1,4]oxazin-4-yl)ethyl]urea (E52)N-(4-Fluorophenyl)-N′-[2-(7-fluoro-2,3- 334dihydrobenzo[1,4]oxazin-4-yl)ethyl]urea (E53)N-(2-Bromophenyl)-N′-[2-(5-fluoro-3,3-dimethyl-2,3- 406, 408dihydroindol-1-yl)ethyl]urea (E54)N-(1-Naphthyl)-N′-[2-(5-fluoro-3,3-dimethyl-2,3- 378dihydroindol-1-yl)ethyl]urea (E55)N-(3-Methylcinnolin-5-yl)-N′-[2-(7-fluoro-2,3- 382dihydrobenzo[1,4]oxazin-4-yl)ethyl]urea (E56)N-(1-Methylisoquinolin-5-yl)-N′-[2-(7-fluoro-2,3- 381dihydrobenzo[1,4]oxazin-4-yl)ethyl]urea (E57)N-(3-Methylisoquinolin-5-yl)-N′-[2-(7-fluoro-2,3- 381dihydrobenzo[1,4]oxazin-4-yl)ethyl]urea (E58)Pharmacological DataIn Vitro Assay

As referenced above, the compounds of the invention are vanilloidreceptor (VR1) antagonists and hence have useful pharmaceuticalproperties. Vanilloid receptor (VR1) antagonist activity can beconfirmed and demonstrated for any particular compound by use ofconventional methods, for example those disclosed in standard referencetexts such as D. Le Bars, M. Gozarin and S. W. Cadden, PharmacologicalReviews, 2001, 53(4), 597-652] or such other texts mentioned herein.

The screen used for the compounds of this invention was based upon aFLIPR based calcium assay, similar to that described by Smart et al.(British Journal of Pharmacology, 2000, 129, 227-230). Transfectedastrocytoma 1321 N1 cells, stably expressing human VR1, were seeded intoFLIPR plates at 25,000 cells/well (96-well plate) and culturedovernight.

The cells were subsequently loaded in medium containing 4 μM Fluo-3 AM(Molecular Probes) for 2 hours, at room temperature, in the dark. Theplates were then washed 4 times with Tyrode containing 1.5 mM calcium,without probenecid. The cells were pre-incubated with compound or buffercontrol at room temperature for 30 minutes. Capsaicin (Sigma) was thenadded to the cells. Compounds having antagonist activity against thehuman VR1 were identified by detecting differences in fluorescence whenmeasured after capsaicin addition, compared with no compound buffercontrols. Thus, for example, in the buffer control capsaicin additionresults in an increase in intracellular calcium concentration resultingin fluorescence. A compound having antagonist activity blocks thecapsaicin binding to the receptor, there is no signalling and thereforeno increase in intracellular calcium levels and consequently lowerfluorescence. pKb values are generated from the IC₅₀ values using theCheng-Prusoff equation.

All compounds tested by the above methodology had pKb>6, preferredcompounds [Examples 1, 3, 10, 11, 12, 14-17, 19, 20-25, 27-33, 37,39-47, 49, 50, 52, 54, 56, 57 and 58] had a pKb>7.0.

1. A compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof:

wherein: P is phenyl, naphthyl or heterocyclyl; R¹ is selected from —H,halo, alkyl, alkoxy, cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl,cycloalkylalkoxy, —CN, —NO₂, —OH, —OCF₃, —CF₃, —NR⁵R⁶, —S(O)_(m)R⁷,—S(O)₂NR⁵R⁶, —OS(O)₂R⁷, —OS(O)₂CF₃, —O(CH₂)_(x)NR⁵R⁶, —C(O)CF₃,—C(O)alkyl, —C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(x)OR⁷,—C(O)(CH₂)_(x)NR⁵R⁶, —C(O)alkoxy, —C(O)NR⁵R⁶, —(CH₂)_(x)C(O)alkoxy,—(CH₂)_(x)OC(O)R⁷, —(CH₂)_(x)OR⁷, —(CH₂)_(x)R⁵R⁶, —(CH₂)_(x)C(O)NR⁵R⁶,—(CH₂)_(x)N(R⁵)C(O)R⁷, —(CH₂)_(x)S(O)₂NR⁵R⁶, —(CH₂)_(x)N(R⁵)S(O)₂R⁷,-ZAr, —(CH₂)_(x)S(O)₂R⁷, —(OCH₂)_(x)S(O)₂R⁷, —N(R⁵)S(O)₂R⁷,—N(R⁵)C(O)R⁷, —(CH₂)_(x)N(R⁵)S(O)₂R⁷, —(CH₂)_(x)N(R⁵)C(O)R⁷ or—(CH₂)_(x)C(O)alkyl; R² is the group:

X is a bond, C, O or NR⁸; R³ is selected from —H, halo, alkyl, alkoxy,cycloalkyl, aryl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy,—CN, —NO₂, —OH, —OCF₃, —CF₃, —NR⁵R⁶, —S(O)_(m)R⁷, —S(O)₂NR⁵R⁶,—OS(O)₂R⁷, —OS(O)₂CF₃, —O(CH₂)_(x)NR⁵R⁶, —C(O)CF₃, —C(O)alkyl,—C(O)cycloalkyl, —C(O)aralkyl, —C(O)Ar, —C(O)(CH₂)_(x)OR⁷,—C(O)(CH₂)_(x)NR⁵R⁶, —C(O)alkoxy, —C(O)NR⁵R⁶, —(CH₂)_(x)C(O)alkoxy,—(CH₂)_(x)OC(O) R⁷, —(CH₂)_(x)OR⁷, —(CH₂)_(x)R⁵R⁶, —(CH₂)_(x)C(O)NR⁵R⁶,—(CH₂)_(x)N(R⁵)C(O)R⁷, —(CH₂)_(x)S(O)₂NR⁵R⁶, —(CH₂)_(x)N(R⁵)S(O)₂R⁷,-ZAr, —(CH₂)_(x)S(O)₂R⁷, —(OCH₂)_(x)S(O)₂R⁷, —N(R⁵)S(O)₂R⁷,—N(R⁵)C(O)R⁷, —(CH₂)_(x)N(R⁵)S(O)₂R⁷, —(CH₂)_(x)N(R⁵)C(O)R⁷ or—(CH₂)_(x)C(O)alkyl; R⁴ is hydrogen or alkyl; R⁵ and R⁶ may be the sameor different and represent H or alkyl or R⁵ and R⁶ together with theatoms to which they are attached form a C₃₋₆azacycloalkane,C₃₋₆(2-oxo)azacycloalkane ring or C₅₋₈ polymethylene chain optionallyinterrupted by heteroatoms such as O or —NR⁸; Z is O, S or NR⁸; R⁷ isalkyl or aryl; R⁸ is hydrogen, alkyl or aryl; n is 2, 3, 4, 5 or 6; p is0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; r is 0, 1 or 2; and x is 0, 1, 2, 3,4, 5 or
 6. 2. A compound of formula (I) as claimed in claim 1, in whichP is phenyl.
 3. A compound of formula (I) as claimed in claim 1, inwhich n is
 2. 4. A compound of formula (I) as claimed in claim 1, inwhich R² is


5. A compound of formula (I) as claimed in claim 4, in which R² isdihydroindolyl, tetrahydroydroquinolinyl or dihydrobenzo[1,4]oxazinyl.6. A compound according to claim 1 in which R³ is halo or alkyl.
 7. Acompound according to claim 1 which is compound Example number E1 to E58or a pharmaceutically acceptable salt or solvate thereof.
 8. A processfor the preparation of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof, which process comprises coupling acompound of formula (II):

in which R¹, P and p are as defined in formula (I) with a compound offormula (III):B—(CH₂)_(n)—R²   (III) in which R² and n are as defined in formula (I)and A and B contain the appropriate functional groups which are capableof reacting together to form the urea moiety; and optionally thereafterif appropriate: (i) removing any protecting groups; (ii) forming apharmaceutically acceptable salt or solvate of the compound so formed.9. A compound of formula (I), as claimed in claim 1 for use in therapy.10. A pharmaceutical composition which comprises a compound of formula(I) as claimed in claim 1 and a pharmaceutically acceptable carrier orexcipient.
 11. The use of a compound of formula (I) as claimed in claim1, or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for the treatment or prophylaxis ofdisorders in which an antagonist of the vanilloid receptor (VR1) isbeneficial.
 12. A method of treating disorders or diseases in which anantagonist of the vanilloid receptor (VR1) is beneficial which comprisesadministering a safe and therapeutically effective amount to a patientin need thereof of a compound of formula (I) as claimed in claim 1, or apharmaceutically effective salt or solvate thereof.